The mu opioid receptor is implicated in the reward, tolerance and withdrawal effects of alcohol and other drugs of abuse. We directly sequenced the human mu opioid receptor locus, OPRM1, to detect natural variation that might affect the function of this receptor or be associated with psychiatric phenotypes related to opioid function. Four DNA sequence variants were found: three amino acid substitutions(Ala6Val [rare], Asn40Asp [frequency 10%], Ser147Cys [rare]) and one intronic variant (IVS2+691G/C [frequency 50%]). OPRM1 alleles, genotypes and haplotypes from three psychiatrically characterized population samples (N = 791) were used to perform association and sib-pair linkage analyses to alcohol dependence. There was no significant association or linkage between OPRM1 and alcohol dependence in any of the three population samples. These results and power calculations strongly suggest that variation at the mu opioid receptor is not involved in vulnerability to DSM-III-R Alcohol Dependence. Variation is being investigated for possible association to response to opiate pharmacotherapy and to variation in opioid function, in collaboration with Stephanie O'Malley, Yale University and in collaboration with COMBINE, amulticenter study of response to naltresone, acamprosate and combined cognitive/behavioral intervention. A study on inherited differences in nociception has been initiated with Ray Dionne & Michael Iadarola of the National Institute of Dental and Craniofacial Research, NIH. A large scale case-control association study on opioid addiction has been completed and these results are in preparation for publication. In another avenue of research, interactions of the genetic variants affecting dopamine function are being investigated for their role in modulating central opioid function. A ten locus DRD2 haplotype predicted opioid addiction in large case control datasets from both Germany and China. COMT Val158Met predicted subchronic pain response and amygdala carfentenyl binding during a pain/stress challenge.